Chlorination of arylamines



Patented Oct. 17, 1933 1,930,754 CHLORINATION OF vARYLADIINES Emeric Havas and Henry R. Lee, South Milwaukee, Wis, assignors to E. I. du Pont de Nemours it; Company, Wilmington, Del., a, cor

poration of Delaware No Drawing.

8 Claims.

lhis application is a continuation. in part of our co-pending application. Ser. No. 531,644,. filed April 20, 1931. In that application we have disclosed a novel, systematic and emcient process for chlorinating o-toluidine, whereby to obtain the chlorinated product in good yield, substantialiy free of isomers and at a considerable saving in the cost of production as .compared with hitherto known processes. The dominant characteristic of said process consisted of converting o-toluidine into a relatively inexpensive acidyl derivative, more particularly the formyl derivative, and then eiiecting dehydration, chlorination, and hydrolysis of the chlorinated formylamino compound in the same medium, without. isolation of any intermediate products. The entire process thusbecomes so systematized that each .step or operation interlinlrs with the next step, and cooperates therewith to eifecta maximum saving of both materials and manipulation. Moreover, the final product is very conveniently separated .fromiso meric chlorination derivatives formed therewith. We have now found that our novel systematic process is of much. wider applicability, and may be used with great success on various other .aromatic amines having a free para-position. Our process is particularly useful in conjunction with arylamines of the benzene series, and hasproven successful even on such arylami-nes, as for instance, cresidine, which hasheretofore apparently never been chlorinated. As for those arylamines which have been directly chlorinated, the hitherto practiced methods of preparing and isolating the p-chloro compound may be illustrated by the following typical process applied specifically to o-toluidine.

l-methyl-2-amino-5-ch1oro-benzene (p-chloroo-toluidine) has been prepared in the art bya process comprising substantially the. following steps:

(a) Conversion of o-toluidine to the corresponding acetyl derivative by treatment with acetic anhydride or glacial acetic acid.

(b) Chlorination of the acetyl compound thus formed in acetic acid by means of chlorine or sodium chlorate and hydrochloric acid (Lelhnan 8; Klotz, Annalen, vol. 231, pages 317,. 318.; Reverdin 8; Crepieux, Berichte, vol. 33, page 2499.)

(0) Separation of the chlorinated .aceto-toluidide from the acetic acid, generally by diluting the reaction mass with water and filtering (Reverdin & Crepieux, ibid.).

(d) Purification of the chlorinated compound; more particularly, separation of the 5-chloro compound irom its isomers and other chlorine deriva- Application January 25, 1932 Serial No. 588,820

tives; generally by recrystallization from alcohol.

(e) Hydrolysis of the chlorinated-aceto-tolui did'e with caustic soda to give the free base, or with hydrochloric acid to give the hydrochloride thereof. (Lellman & Klotz and Reverdin & Crepieux, above).

(1) Final purification by steam distillation.

In British Patent No. 294,462, a modification of the above processes has been proposed, whereby instead of converting the ortho-toluidine in step (a) into its acetyl derivative, it is converted into the corresponding o-toluene-sulfonyl derivative, the remaining steps being substantially as above outlined. It is claimed that this modification produces a more homogeneous product, avoiding Z0 the formation of isomers or higher halogenderivatives. The yield, however, has not been stated, and it is not clear if no isomers have been formed at all in the process, 'or if a more eflicient separation of the 5-chloro-2-acidylamino-l toluene from its isomers is obtained.

In all the above processes large quantities of glacial acetic acidare necessary. A large portion of this is practically completely'wasted in the dilution step, since recovery of acetic acid from a dilute solution is a costly operation, and will at best return only a small fractionof the initial cost of the acid.

In those processes alsolarge quantities'of hydrochloric acid are required for hydrolysis, because of the diluting action ,eifected by jthe acetic acid and water physically held in the filter cake.- Although 1 mole of HCl is formed in the chlorination step for each mole of toluidine chlorinated, this is entirely lost in the filtration step and therefore is not available for the hydrolysis step. Furthermore, the stepof separating the chlorinated acidylamino compound from the acetic acid itself also constitutes a waste since it consumes labor, time, and plant equipment. On the other hand, this step cannot be dispensed with, because otherwise excessively large and impractical quantities of hydrochloric acid wouldbe required to eifect hydrolysis, in view of the large quantity of acetic acid present in the mass and in view of its diluting action upon the HCl.

Another big disadvantage of all these processes is that the acidylating agents used, glacial acetic acid, acetic anhydride, ortho-toluene-sulfo chloride and the like, are expensive, and are practically completely wasted. I

It is'accordingly an object, of this invention to provide an eificient and systematic process for chlorinating arylamines having a free paraposition.

It is a further object of this invention to provide a process for chlorinating arylainines whereby the corresponding parachloro-arylamine body is prepared in good yield and may be economically and effectively separated from any isomeric chloro derivatives formed therewith.

It is a further object of this invention to provide a process for chlorinating arylamines wherein each step or operation cooperates'with the next step to produce a maximum economy of raw materials and manipulation and to reduce amine body is first converted into its formyl derivative by reacting upon the same with a concentrated solution of formic acid. The mass is then suspended in an organic solvent which is a solvent for the formylamino body, immiscible with water, and inert toward chlorination in the absence of .a catalyst. As typical examples of such organic solvent, benzene,.'toluene, and chlorobenzene may be mentioned. The mass is then heated to evaporate oil the water formed in the formylation step, cooled, and a chlorinating agent, such as chlorine gas or sulfuryl chloride is introduced, until the calculated amount of chlorine has been absorbed. At this stage the mass contains the p-chloro derivative of the particular aryl-formylamide started with, in addition to some isomeric chlorine derivatives, all dissolved in the organic medium. This mass is now mixed with water and hydrochoric acid and is heated, whereby hydrolysis of the formyl group, formation of the hydrochloride of the amine, and simultaneous separation of the mass into three phases takes place. It is a characteristic feature of our invention and a most highly convenient circumstance that in most cases the hydrochloride of the p-chloro-arylamino body is less soluble in water than the hydrochlorides of the isomeric chloro derivatives. Consequently, the hydrochloride of the p-chloro-arylamine body separates from the mixture as a solid phase, substantiallyv free of isomers. The isomeric chloro derivatives, in the form of their hydrochlorides are transferred from the organic medium, which separates as an oily phase, into the aqueous phase and remain dissolved therein together with any residual hydrochloric acid and the formic acid formed by hydrolysis. The separation of the three phasesis now a very simple matter, as will be readily understood to anyone skilled in the art. The

solid phase is isolated by filtration, and needs no further treatment except washing, and, where the free base is desired, treatment with caustic alkali. Depending on whether the last step is used or not, the product is substantially pure p-chloro-arylamine or the hydrochloride there of. The organic layer may be separated by settling and decantation and steam distilled to recover the organic solvent in substantially pure form. The aqueous phase may be discarded or treated in any suitable manner to recover its constituents.

The cooperative and systematic interlinkage of the various steps in our process will now become more readily apparent from the following discussion.

The first characteristic and profitable feature of our invention is the selection of formic acid as acidylating agent. The immediate advantage of this selection is that formic acid costs considerably less, mole for mole, than glacial acetic acid, acetic anhydride, or o-toluene-sulfochloride.

Another important advantage made possible by the use of formic acid is the fact that the formyl compounds of most arylamines are highly soluble in water-insoluble organic solvents such as toluene or benzene. This permits performing the entire process, namely, the chlorination and the hydrolysis, in an inert organic medium, such as for example, toluene, which can be efficiently recovered at the end' of the reaction. Moreover, the use of toluene as a solvent in the chlorination step enables one to eliminate the heretofore necessary step of separating the chlorinated compound from the solvent before hydrolysis. Thus the materials, labor and time heretofore consumed in this step are saved. Furthermore, the use of toluene saves the hydrochloric acid formed in the chlorination step. Also, the formyl group is more readily hydrolyzed than the acetyl group. Consequently, the quantity of hydrochloric acid that must be added in the hydrolysis step is reduced to a mere fraction of the quantity required in heretofore known processes.

Finally, the use of an anhydrous organic medium reduces the volumes of liquid to be handled to a minimum, which in itself is a great advantage, but possesses the further advantage that only a relatively small quantity of water is required in the hydrolysis step. Therefore, very little of the hydrolyzed p-chloro derivative is soluble in the aqueous layer, and this compound readily separatesfrom isomers without resort to any special intermediary separation steps, such as isolation of all the chloro bodies in solidform,'and fractionally recrystallizing the same from alcohol.

Other material advantages from our novel systematized process will appear from the detailed description below.

Without limiting our invention to any particular procedure, the following examples, in which partsby weight are given, will serve to illustrate 130 our systematic method in its preferred form.

Emample 1 321 parts of o-toluidine, and 180 parts of 90% formic acid are heated together at about 100 to 5 103 C. for about 3 hours. The mass is then cooled to about 70 C., and 750 parts of tolueneare added. The mass is now heated to distill off the excess of formic acid as well as any water present, and then cooled to about 60 C. Additional toluene is now introduced into the 'mass to bring the total quantity of toluene to about 1400 parts. The toluene diluted mass is cooled to about 20 C., and chlorine gas is passed through the mixture until about 234: parts have been consumed. parts of water are now added, and 260 parts of an aqueoushydrochloric acid solution (20 Be.) are now introduced. The mass is heated at about 60 C. for about 2 hours, cooled to 20 C. and filtered. The filter cake is 5 Example 2 242 parts of p-Xylidine and 120 formic acid 103 C. for about 3 hours. The mass is then cooled to about 70 C. and 500 parts of toluene are added. The mass is now heated to distill on the excess of formic acid as well as any water that is present and then cooled to about C. Additional toluene is now introduced into the mass to bring the totalquantity oftoluene. to about 1800 parts. The toluene-diluted mass is cooled to about 20 C. and chlorine gas is passed into the mixture at 20 C. until 142 parts have been consumed. 50 parts of water are now added 170 parts of an aqueous hydrochloric acid solution (20 as.) are introduced. The mass is heated at about ISO- C. cooled to 20 C. and filtered. The filter cake stitutes the hydrochloride of 5-chl0ro-2- amino-1,4lxylene in high yield and of sufiicient purity to be applicable directly for technical purposes.

parts of filtrate consists of two phases. (1) An aqueous phase containing dissolved therein the excess hydrochloric acid and the hydrochloride of any isomeric chloro-xylidines formed, and (2) an oily phase from which the toluene may be recovered in pure form by steam distillation.

Example 3 C. and chlorine gas is passed into the mixture at.

C. until about 142 parts have been consumed. =0 parts of water are now added and 170 parts i an aqueous hydrochloric acid solution (20 B.) re introduced. The mass is heated at about 50-65" C. for about 2 hours, cooled to 20 C. and filtered. The filter cake constitutes the hydrochloride of S-chlorc-Z-amino-l-methoxy-4-toluone in yield and of suhicient purity to be applicable directly for technical purposes.

The filtrate consists of two phases: (1) An aqueous phase containing dissolved therein the excess hydrochloric acid and the hydrochloride of any isomeric chloro-cresidines formed, and 2) an oily phase from which the toluene may be recovered in pure form by steam distillation.

It will thus be seen that the handling of materials to a minimum, saves hydrochloric acid, replaces the costly acidylating agent by the comparatively cheap formic acid, uses an inexpensive solvent for the reaction, and enables the recovery of the same without waste are heated together at about for about 2 hours,

our novel, systematic process is exceedingly simple in operation, reduces and at verylittle cost. Due to the great reduction in liquid volumes handled and the substantial absence. of dilute solvents, the separation of p-chloro-arylamine body from its isomers is more complete and the product is obtained in a com.-

paratively pure state.

It will be understood that many variations and modifications are possible in the specific procedure disclosed, without departing from the spirit of this invention. i

Thus, instead of chlorine gas, other chlorinating' agents which are adapted for use in anh drous media may be used, for instance, suifuryl solvent may be used, providedit is a good solvent for the particular aryl-formam-ide, immiscible with water, and not readily chlorinated at; low

temperatures in the absence of a catalyst. Benof course, the product precipitates the form of hydrochloride.

- It will be further understood, that although we have illustrated our invention specifically with respectto benzenoid arylamines, such as o-tol-uidine, p-xylidine and cresid ine, our process is applicable with equal advantage to the chlorin tion of other arylamines having a free p-position.

in each step cooperates with the next step to produce a highly efficient, economical and unified result.

In the claims below it should be understood that where we speak of a p-chloro-arylamine body we mean to include such body both in basic form or in the form of a salt thereof.

We claim:

1. A process for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with a chlorinating agent upon which is substantially inert toward chlorine, adding an aqueous non-oxidizing inorganic acid solution to efiect hydrolysis of the formyl group, and recovering the precipitated salt of the p-chloro-arylamine.

2. A process for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with chlorine gas upon a solution of a formyl-amino-aryl body of the benzene series, having a free position para to the amino group, in toluene, adding an aqueous non-oxidiz ing inorganic acid solution, warming to efl'ect hydrolysis of the formyl group, and recovering the precipitated salt of the p-chloro-arylamine.

3. A process for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with a chlorinating agent upon a solution of a formyl-amino-aryl body of the benzene series in an anhydrous benzenoid solvent which is substantially inert toward chlorine, adding an aqueous hydrochloric effect hydrolysis of the formyl group, and refor Instance sulfuric: acid. In case,

4 covering the precipitated hydrochloride of the p-chloro-arylamine.

4. A process for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with chlorine gas upon a solution of a formyl-amino-aryl body of the benzene series, having a free position para to the amino group, in toluene, adding an aqueous hydrochloric acid solution, warming to effect hydrolysis of the formyl group, and recovering the'precipitated hydrochloride of the p chloro-arylamine.

5. A process for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with a chlorinating agent upon a solution of a formyl-amino-aryl body of the benzene series having a free position para to the amino group, in an anhydrous organic solvent which is substantially immiscible with water and inert toward chlorine atroom temperature and in the absence of catalysts, adding an aqueous non-oxidizing inorganic acid solution to effect hydrolysis of the formyl group, and recovering the precipitated salt of the p-chloro-arylamine.

6. The process of preparing ap-chloro-arylamino body of the benzene series which comprises reacting upon an arylamino body of the benzene series, having a free-position para to the amino group, with formic acid to "produce the corresponding formylarnino-aryl body, dissolving the latter in toluene, heating the mixture to eliminate excess formic acid and water, passing chlorine gas into the toluene solution of the formylamino-aryl body, adding an aqueous non-oxidizing inorganic acid solution, warming the mass to efiecthydrolysis of the formyl group, and filtering to isolate the salt of the p-chloro-arylamine.

'7. A process. for preparing a p-chloro-arylamine body of the benzene series, which comprises reacting with a chlorinating agent upon a solution of a formyl-amino-aryl body of the benzene series having a free position para to the amino group, in an anhydrous organic solvent which is substantially immiscible with water and inert toward chlorine at room temperature and in the absence of catalysts, adding an aqueous hydrochloric acid solution to effect hydrolysis of theformyl group, and recovering the precipitated'hydrochloride of the p-chloro-arylamine.

8. The process of preparing a p-chloro-arylamino body of the benzene series which comprises reacting upon -an arylamino body of the benzene series having a free position para to the amino group, with formic acid to produce the corresponding forrnylamino-aryl body, dissolving the latter in toluene, heating the mixture to eliminate excess formic acid and water, passing chlorine gas into the amino-aryl body, adding an aqueous hydrochloric acid solution, warming the mass to efiect hydrolysis of the formyl group, and filtering to isolate the hydrochloride of the p-chloro-arylamine.

ENLERIC HAVAS. HENRY R. LEE.

toluene solution of the formyl- 

